Introduction The immune system has evolved to protect the organism from invasion by many different pathogens (e.g., viruses, bacteria, and helminthes) and from the emergence of tumors. However, it can also react in an exacerbated manner against self and non-self host components, leading to the onset of autoimmune pathologies (e.g., juvenile diabetes and systemic lupus erythematosus) and chronic inflammatory diseases (e.g., Crohn disease). Large-scale immuno-phenotyping studies in humans have

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... ently analyzed inter-and intra-individual variations of leukocyte subsets before, during, and after immunological challenge. Surprisingly, these studies reported a relative harmony of the immune profile of each individual over several months, revealing that after a response the immunological parameters return to their initial state [1] . The immune system therefore tends to stability, as recently proposed by the equilibrium model of immunity of Eberl [2] . According to this model, different types of immune reactions (i.e., "type" 1 against intra-cellular pathogens, and "type 2" and "type 3" against large and small extra-cellular microorganisms, respectively) in- Abstract The generation and function of immuno-suppressive regulatory T lymphocytes (Treg), which can differentiate in the thymus (tTreg) or in the periphery (pTreg), are regulated in an age-dependent manner. tTreg are produced at high levels in the first weeks of age, when they expand and colonize secondary lymphoid organs and peripheral tissues to protect the organism from autoimmune diseases and to promote tissue repair. Once this population of Treg is operational in the periphery, at puberty, thymic output of Treg declines, but self-reactive tTreg generated early on in life are maintained over time and play a major role in preserving homeostasis of the immune system. Extra-thymic pTreg differentiation declines later on in life. pTreg generated throughout life mainly protect the organism from chronic inflammation and the semi-allogeneic fetus from rejection. In this review, agedependent modulation of the production and function of these two populations of Treg is described.